Cerium Oxide Nanoparticles Attenuate Diabetic Nephropathy in Rats by Reducing Oxidative Stress, Improving Dyslipidemia, and Modulating PKM2 and KIM-1
Abstract
Objectives: Oxidative stress and inflammation play important role in pathophysiology of Diabetic nephropathy (DN). Nanoparticles, including cerium oxide nanoparticles (CeO2NPs) which reduce oxidative stress and inflammation, are increasingly used in treatment of the diseases. Therefore, this study aims to assess the preventive potential of CeO2NPs' in a DN animal model by examining their effects on glucose, lipids, oxidative stress, and kidney damage markers.
Methods: Diabetes was induced in rats using streptozocin (STZ). Rats were divided into normal control (N-Cnt), diabetic control (D-Cnt), and CeO2NPs-treated groups (D-CeO2, 60 mg/kg). Fasting blood glucose (FBG) levels were measured at baseline and day 35. Also serum lipid profiles, including TC, TG, HDL-C, and LDL-C, were assessed. In kidney tissue, the activities of the antioxidant enzymes (SOD, CAT, GPx), the levels of malondialdehyde (MDA), total antioxidant capacity (TAC), and mRNA expression of pyruvate kinase M2 (PKM2) and kidney injury molecule-1 (KIM-1) were determined.
Results: CeO2NPs treatment in D-CeO2NPs rats significantly reduced FBG and improved the lipid profile (decreased TC, TG, LDL-C; increased HDL-C, P<0.05). CeO2NPs also attenuated oxidative stress (increased SOD, CAT, GPx, TAC; reduced MDA, P<0.05) and downregulated PKM2 and KIM-1 mRNA expression (P<0.05) compared to D-Cnt rats.
Conclusions: CeO2NPs demonstrate protective effects against DN in this rat model through ameliorating hyperglycemia, dyslipidemia, and oxidative stress, and modulating the expression of renal injury markers. These findings suggest that CeO2NPs may have therapeutic potential for DN, warranting further investigation into their mechanisms and clinical applicability.
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8. Xu C, Qu X. Cerium oxide nanoparticle: a remarkably versatile rare earth nanomaterial for biological applications. NPG Asia Materials. 2014;6(3):e90-e. https://doi.org/10.1038/am.2013.88
9. Yi L, Yu L, Chen S, Huang D, Yang C, Deng H, et al. The regulatory mechanisms of cerium oxide nanoparticles in oxidative stress and emerging applications in refractory wound care. Front Pharmacol. 2024;15:1439960. https://doi.org/10.3389/fphar.2024.1439960
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11. Tu C, Wang L, Wei L. The Role of PKM2 in Diabetic Microangiopathy. Diabetes Metab Syndr Obes. 2022;15:1405-12. https://doi.org/10.2147/DMSO.S366403
12. Bonventre JV. Kidney Injury Molecule-1 (KIM-1): a specific and sensitive biomarker of kidney injury. Scand J Clin Lab Invest Suppl. 2008;241(sup241):78-83. https://doi.org/10.1080/00365510802145059
13. Greenberg JH, Abraham AG, Xu Y, Schelling JR, Feldman HI, Sabbisetti VS, et al. Plasma Biomarkers of Tubular Injury and Inflammation Are Associated with CKD Progression in Children. J Am Soc Nephrol. 2020;31(5):1067-77. https://doi.org/10.1681/ASN.2019070723
14. Golmohammadi M, Ahmadi SJ, Towfighi J. Catalytic supercritical water destructive oxidation of tributyl phosphate: Study on the effect of operational parameters. J Supercrit Fluids. 2018;140:32-40. https://doi.org/10.1016/j.supflu.2018.05.022
15. Golmohammadi M, Towfighi J, Hosseinpour M, Ahmadi SJ. An investigation into the formation and conversion of metal complexes to metal oxide nanoparticles in supercritical water. J Supercrit Fluids. 2016;107:699-706. https://doi.org/10.1016/j.supflu.2015.07.034
16. Alimoradian A, Karami H, Latifi SA, Ghazavi A, Akbari A, Pilevar Z, et al. Saffron has a therapeutic effect on nephropathy by regulating the expression of TLR4, S100A8, and HMGB1 genes and reducing oxidative stress in diabetic rats. Acta Biochim Iran. 2024;2(2):78-86. https://doi.org/10.18502/abi.v2i2.17934
17. Wu T, Ding L, Andoh V, Zhang J, Chen L. The Mechanism of Hyperglycemia-Induced Renal Cell Injury in Diabetic Nephropathy Disease: An Update. Life (Basel). 2023;13(2). https://doi.org/10.3390/life13020539
18. Alghamdi J, El-Refaei M. Effects of gold and cerium oxide nanoparticles on type 1 diabetes in experimental mice. Pak J Biol Sci. 2020;23(7):959-67. https://doi.org/10.3923/pjbs. 020.959.967
19. Pourkhalili N, Hosseini A, Nili-Ahmadabadi A, Hassani S, Pakzad M, Baeeri M, et al. Biochemical and cellular evidence of the benefit of a combination of cerium oxide nanoparticles and selenium to diabetic rats. World J Diabetes. 2011;2(11):204-10. https://doi.org/10.4239/wjd.v2.i11.204
20. Lopez-Pascual A, Urrutia-Sarratea A, Lorente-Cebrian S, Martinez JA, Gonzalez-Muniesa P. Cerium Oxide Nanoparticles Regulate Insulin Sensitivity and Oxidative Markers in 3T3-L1 Adipocytes and C2C12 Myotubes. Oxid Med Cell Longev. 2019;2019:2695289. https://doi.org/10.1155/2019/2695289
21. Elendu C, John Okah M, Fiemotongha KDJ, Adeyemo BI, Bassey BN, Omeludike EK, et al. Comprehensive advancements in the prevention and treatment of diabetic nephropathy: A narrative review. Medicine (Baltimore). 2023;102(40):e35397. https://doi.org/10.1097/MD.0000000000035397
22. Gai Z, Wang T, Visentin M, Kullak-Ublick GA, Fu X, Wang Z. Lipid Accumulation and Chronic Kidney Disease. Nutrients. 2019;11(4). https://doi.org/10.3390/nu11040722
23. Bashandy SAE, Elbaset MA, Ibrahim FAA, Abdelrahman SS, Moussa SAA, El-Seidy AMA. Management of cardiovascular disease by cerium oxide nanoparticles via alleviating oxidative stress and adipokine abnormalities. Sci Rep. 2025;15(1):5709. https://doi.org/10.1038/s41598-025-85794-6
24. Parra-Robert M, Casals E, Massana N, Zeng M, Perramon M, Fernandez-Varo G, et al. Beyond the Scavenging of Reactive Oxygen Species (ROS): Direct Effect of Cerium Oxide Nanoparticles in Reducing Fatty Acids Content in an In Vitro Model of Hepatocellular Steatosis. Biomolecules. 2019;9(9). https://doi.org/10.3390/biom9090425
25. Yang Q, Luo X, Wang Y, Li H, Cong L, Sun Y. Cerium oxide nanoparticles protect against obesity-induced ovarian dysfunction. Appl Mater Today. 2021;22:100973. https://doi.org/10.1016/j.apmt.2021.100973
26. Caturano A, D'Angelo M, Mormone A, Russo V, Mollica MP, Salvatore T, et al. Oxidative Stress in Type 2 Diabetes: Impacts from Pathogenesis to Lifestyle Modifications. Curr Issues Mol Biol. 2023;45(8):6651-66. https://doi.org/10.3390/cimb45080420
27. Daehn IS, Ekperikpe US, Stadler K. Redox regulation in diabetic kidney disease. Am J Physiol Renal Physiol. 2023;325(2):F135-F49. https://doi.org/10.1152/ajprenal.00047.2023
28. Sepanjnia A, Ghasemi H, Mohseni R, Ranjbar A, Shabani F, Salimi F, et al. Effect of Cerium Oxide Nanoparticles on Oxidative Stress Biomarkers in Rats' Kidney, Lung, and Serum. Iran Biomed J. 2020;24(4):251-6. https://doi.org/10.29252/ibj.24.4.251
29. Abdelhameed M, Bashandy S, Ibrahim F, Morsy F, Farid O, Elbaset M. The Pivotal role of Cerium oxide nanoparticles in thioacetamide-induced hepatorenal injury in rat. Egypt J Chem. 2022;0(0):0-. https://doi.org/10.21608/ejchem.2022.115482.5242
30. Gordin D, Shah H, Shinjo T, St-Louis R, Qi W, Park K, et al. Characterization of Glycolytic Enzymes and Pyruvate Kinase M2 in Type 1 and 2 Diabetic Nephropathy. Diabetes Care. 2019;42(7):1263-73. https://doi.org/10.2337/dc18-2585
31. Xie W, He Q, Zhang Y, Xu X, Wen P, Cao H, et al. Pyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injury. Cell Death Dis. 2023;14(10):663. https://doi.org/10.1038/s41419-023-06195-z
32. Park YS, Han JH, Park JH, Choi JS, Kim SH, Kim HS. Pyruvate Kinase M2: A New Biomarker for the Early Detection of Diabetes-Induced Nephropathy. Int J Mol Sci. 2023;24(3):2683. https://doi.org/10.3390/ijms24032683
33. Chen DQ, Han J, Liu H, Feng K, Li P. Targeting pyruvate kinase M2 for the treatment of kidney disease. Front Pharmacol. 2024;15:1376252. https://doi.org/10.3389/fphar.2024.1376252
34. Anandkumar DG, Dheerendra PC, Vellakampadi D, Ramanathan G. Kidney injury molecule-1; is it a predictive marker for renal diseases? J nephropharmacol. 2023;12(2):e10572-e. https://doi.org/10.34172/npj.2023.10572
35. Khan FA, Fatima SS, Khan GM, Shahid S. Evaluation of kidney injury molecule-1 as a disease progression biomarker in diabetic nephropathy. Pak J Med Sci. 2019;35(4):992-6. https://doi.org/10.12669/pjms.35.4.154
36. Li L, Tang L, Yang X, Chen R, Zhang Z, Leng Y, et al. Gene Regulatory Effect of Pyruvate Kinase M2 is Involved in Renal Inflammation in Type 2 Diabetic Nephropathy. Exp Clin Endocrinol Diabetes. 2020;128(9):599-606. https://doi.org/10.1055/a-1069- 290
37. Wang M. PKM2-induced protection from hyperglycaemia. Nat Rev Nephrol. 2022;18(4):199. https://doi.org/10.1038/s41581-022-00556-1
38. Gauer S, Urbschat A, Gretz N, Hoffmann SC, Kränzlin B, Geiger H, et al. Kidney Injury Molecule-1 Is Specifically Expressed in Cystically-Transformed Proximal Tubules of the PKD/Mhm (cy/+) Rat Model of Polycystic Kidney Disease. Int J Mol Sci. 2016;17(6):802. https://doi.org/doi:10.3390/ijms17060802
39. Zhu Y, Yang Y, Lan Y, Yang Z, Gao X, Zhou J. The role of PKM2-mediated metabolic reprogramming in the osteogenic differentiation of BMSCs under diabetic periodontitis conditions. Stem Cell Res Ther. 2025;16(1):186. https://doi.org/10.1186/s13287-025-04301-w
2. Pappachan JM, Fernandez CJ, Ashraf AP. Rising tide: The global surge of type 2 diabetes in children and adolescents demands action now. World J Diabetes. 2024;15(5):797-809. https://doi.org/10.4239/wjd.v15.i5.797
3. Samsu N. Diabetic Nephropathy: Challenges in Pathogenesis, Diagnosis, and Treatment. Biomed Res Int. 2021;2021:1497449. https://doi.org/10.1155/2021/1497449
4. Jin Q, Liu T, Qiao Y, Liu D, Yang L, Mao H, et al. Oxidative stress and inflammation in diabetic nephropathy: role of polyphenols. Front Immunol. 2023;14:1185317. https://doi.org/10.3389/fimmu.2023.1185317
5. Irazabal MV, Torres VE. Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease. Cells. 2020;9(6). https://doi.org/10.3390/cells9061342
6. Huang R, Fu P, Ma L. Kidney fibrosis: from mechanisms to therapeutic medicines. Signal Transduct Target Ther. 2023;8(1):129. https://doi.org/10.1038/s41392-023-01379-7
7. Nelson BC, Johnson ME, Walker ML, Riley KR, Sims CM. Antioxidant Cerium Oxide Nanoparticles in Biology and Medicine. Antioxidants (Basel). 2016;5(2). https://doi.org/10.3390/antiox5020015
8. Xu C, Qu X. Cerium oxide nanoparticle: a remarkably versatile rare earth nanomaterial for biological applications. NPG Asia Materials. 2014;6(3):e90-e. https://doi.org/10.1038/am.2013.88
9. Yi L, Yu L, Chen S, Huang D, Yang C, Deng H, et al. The regulatory mechanisms of cerium oxide nanoparticles in oxidative stress and emerging applications in refractory wound care. Front Pharmacol. 2024;15:1439960. https://doi.org/10.3389/fphar.2024.1439960
10. Alquraishi M, Puckett DL, Alani DS, Humidat AS, Frankel VD, Donohoe DR, et al. Pyruvate kinase M2: A simple molecule with complex functions. Free Radic Biol Med. 2019;143:176-92. https://doi.org/10.1016/j.freeradbiomed.2019.08.007
11. Tu C, Wang L, Wei L. The Role of PKM2 in Diabetic Microangiopathy. Diabetes Metab Syndr Obes. 2022;15:1405-12. https://doi.org/10.2147/DMSO.S366403
12. Bonventre JV. Kidney Injury Molecule-1 (KIM-1): a specific and sensitive biomarker of kidney injury. Scand J Clin Lab Invest Suppl. 2008;241(sup241):78-83. https://doi.org/10.1080/00365510802145059
13. Greenberg JH, Abraham AG, Xu Y, Schelling JR, Feldman HI, Sabbisetti VS, et al. Plasma Biomarkers of Tubular Injury and Inflammation Are Associated with CKD Progression in Children. J Am Soc Nephrol. 2020;31(5):1067-77. https://doi.org/10.1681/ASN.2019070723
14. Golmohammadi M, Ahmadi SJ, Towfighi J. Catalytic supercritical water destructive oxidation of tributyl phosphate: Study on the effect of operational parameters. J Supercrit Fluids. 2018;140:32-40. https://doi.org/10.1016/j.supflu.2018.05.022
15. Golmohammadi M, Towfighi J, Hosseinpour M, Ahmadi SJ. An investigation into the formation and conversion of metal complexes to metal oxide nanoparticles in supercritical water. J Supercrit Fluids. 2016;107:699-706. https://doi.org/10.1016/j.supflu.2015.07.034
16. Alimoradian A, Karami H, Latifi SA, Ghazavi A, Akbari A, Pilevar Z, et al. Saffron has a therapeutic effect on nephropathy by regulating the expression of TLR4, S100A8, and HMGB1 genes and reducing oxidative stress in diabetic rats. Acta Biochim Iran. 2024;2(2):78-86. https://doi.org/10.18502/abi.v2i2.17934
17. Wu T, Ding L, Andoh V, Zhang J, Chen L. The Mechanism of Hyperglycemia-Induced Renal Cell Injury in Diabetic Nephropathy Disease: An Update. Life (Basel). 2023;13(2). https://doi.org/10.3390/life13020539
18. Alghamdi J, El-Refaei M. Effects of gold and cerium oxide nanoparticles on type 1 diabetes in experimental mice. Pak J Biol Sci. 2020;23(7):959-67. https://doi.org/10.3923/pjbs. 020.959.967
19. Pourkhalili N, Hosseini A, Nili-Ahmadabadi A, Hassani S, Pakzad M, Baeeri M, et al. Biochemical and cellular evidence of the benefit of a combination of cerium oxide nanoparticles and selenium to diabetic rats. World J Diabetes. 2011;2(11):204-10. https://doi.org/10.4239/wjd.v2.i11.204
20. Lopez-Pascual A, Urrutia-Sarratea A, Lorente-Cebrian S, Martinez JA, Gonzalez-Muniesa P. Cerium Oxide Nanoparticles Regulate Insulin Sensitivity and Oxidative Markers in 3T3-L1 Adipocytes and C2C12 Myotubes. Oxid Med Cell Longev. 2019;2019:2695289. https://doi.org/10.1155/2019/2695289
21. Elendu C, John Okah M, Fiemotongha KDJ, Adeyemo BI, Bassey BN, Omeludike EK, et al. Comprehensive advancements in the prevention and treatment of diabetic nephropathy: A narrative review. Medicine (Baltimore). 2023;102(40):e35397. https://doi.org/10.1097/MD.0000000000035397
22. Gai Z, Wang T, Visentin M, Kullak-Ublick GA, Fu X, Wang Z. Lipid Accumulation and Chronic Kidney Disease. Nutrients. 2019;11(4). https://doi.org/10.3390/nu11040722
23. Bashandy SAE, Elbaset MA, Ibrahim FAA, Abdelrahman SS, Moussa SAA, El-Seidy AMA. Management of cardiovascular disease by cerium oxide nanoparticles via alleviating oxidative stress and adipokine abnormalities. Sci Rep. 2025;15(1):5709. https://doi.org/10.1038/s41598-025-85794-6
24. Parra-Robert M, Casals E, Massana N, Zeng M, Perramon M, Fernandez-Varo G, et al. Beyond the Scavenging of Reactive Oxygen Species (ROS): Direct Effect of Cerium Oxide Nanoparticles in Reducing Fatty Acids Content in an In Vitro Model of Hepatocellular Steatosis. Biomolecules. 2019;9(9). https://doi.org/10.3390/biom9090425
25. Yang Q, Luo X, Wang Y, Li H, Cong L, Sun Y. Cerium oxide nanoparticles protect against obesity-induced ovarian dysfunction. Appl Mater Today. 2021;22:100973. https://doi.org/10.1016/j.apmt.2021.100973
26. Caturano A, D'Angelo M, Mormone A, Russo V, Mollica MP, Salvatore T, et al. Oxidative Stress in Type 2 Diabetes: Impacts from Pathogenesis to Lifestyle Modifications. Curr Issues Mol Biol. 2023;45(8):6651-66. https://doi.org/10.3390/cimb45080420
27. Daehn IS, Ekperikpe US, Stadler K. Redox regulation in diabetic kidney disease. Am J Physiol Renal Physiol. 2023;325(2):F135-F49. https://doi.org/10.1152/ajprenal.00047.2023
28. Sepanjnia A, Ghasemi H, Mohseni R, Ranjbar A, Shabani F, Salimi F, et al. Effect of Cerium Oxide Nanoparticles on Oxidative Stress Biomarkers in Rats' Kidney, Lung, and Serum. Iran Biomed J. 2020;24(4):251-6. https://doi.org/10.29252/ibj.24.4.251
29. Abdelhameed M, Bashandy S, Ibrahim F, Morsy F, Farid O, Elbaset M. The Pivotal role of Cerium oxide nanoparticles in thioacetamide-induced hepatorenal injury in rat. Egypt J Chem. 2022;0(0):0-. https://doi.org/10.21608/ejchem.2022.115482.5242
30. Gordin D, Shah H, Shinjo T, St-Louis R, Qi W, Park K, et al. Characterization of Glycolytic Enzymes and Pyruvate Kinase M2 in Type 1 and 2 Diabetic Nephropathy. Diabetes Care. 2019;42(7):1263-73. https://doi.org/10.2337/dc18-2585
31. Xie W, He Q, Zhang Y, Xu X, Wen P, Cao H, et al. Pyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injury. Cell Death Dis. 2023;14(10):663. https://doi.org/10.1038/s41419-023-06195-z
32. Park YS, Han JH, Park JH, Choi JS, Kim SH, Kim HS. Pyruvate Kinase M2: A New Biomarker for the Early Detection of Diabetes-Induced Nephropathy. Int J Mol Sci. 2023;24(3):2683. https://doi.org/10.3390/ijms24032683
33. Chen DQ, Han J, Liu H, Feng K, Li P. Targeting pyruvate kinase M2 for the treatment of kidney disease. Front Pharmacol. 2024;15:1376252. https://doi.org/10.3389/fphar.2024.1376252
34. Anandkumar DG, Dheerendra PC, Vellakampadi D, Ramanathan G. Kidney injury molecule-1; is it a predictive marker for renal diseases? J nephropharmacol. 2023;12(2):e10572-e. https://doi.org/10.34172/npj.2023.10572
35. Khan FA, Fatima SS, Khan GM, Shahid S. Evaluation of kidney injury molecule-1 as a disease progression biomarker in diabetic nephropathy. Pak J Med Sci. 2019;35(4):992-6. https://doi.org/10.12669/pjms.35.4.154
36. Li L, Tang L, Yang X, Chen R, Zhang Z, Leng Y, et al. Gene Regulatory Effect of Pyruvate Kinase M2 is Involved in Renal Inflammation in Type 2 Diabetic Nephropathy. Exp Clin Endocrinol Diabetes. 2020;128(9):599-606. https://doi.org/10.1055/a-1069- 290
37. Wang M. PKM2-induced protection from hyperglycaemia. Nat Rev Nephrol. 2022;18(4):199. https://doi.org/10.1038/s41581-022-00556-1
38. Gauer S, Urbschat A, Gretz N, Hoffmann SC, Kränzlin B, Geiger H, et al. Kidney Injury Molecule-1 Is Specifically Expressed in Cystically-Transformed Proximal Tubules of the PKD/Mhm (cy/+) Rat Model of Polycystic Kidney Disease. Int J Mol Sci. 2016;17(6):802. https://doi.org/doi:10.3390/ijms17060802
39. Zhu Y, Yang Y, Lan Y, Yang Z, Gao X, Zhou J. The role of PKM2-mediated metabolic reprogramming in the osteogenic differentiation of BMSCs under diabetic periodontitis conditions. Stem Cell Res Ther. 2025;16(1):186. https://doi.org/10.1186/s13287-025-04301-w
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| Issue | Vol 2 No 4 (2024) | |
| Section | Original Articles | |
| Keywords | ||
| Cerium oxide nanoparticles Diabetic nephropathy Oxidative stress PKM2 KIM-1 | ||
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How to Cite
1.
Amri J, Emadi A, Rezaei N, Salemi Z. Cerium Oxide Nanoparticles Attenuate Diabetic Nephropathy in Rats by Reducing Oxidative Stress, Improving Dyslipidemia, and Modulating PKM2 and KIM-1. ABI. 2024;2(4):196-203.
